In the early postnatal period, cardiomyocytes undergo rapid growth and maturation that is essential for normal cardiac development. Coincident with cardiomyocyte differentiation and cell cycle withdrawal is the establishment of the N-cadherin-based adherens junction (AJ), a critical determinant of intercalated disc (ID) structure that provides the end-to-end connection between cardiomyocytes. AJ are stabilized at the ID by the dynamic I has binding of the intracellular cadherin domain to the actin cytoskeleton via beta- and alpha-catenins. To explore the role of mechanotransduction in cardiac development and homeostasis, we developed a novel animal model (alpha-cat double knockout (DKO)) in which both cytoskeletal linker proteins alphaE- and alphaT-catenin were depleted in the heart. We discovered that alpha-catenin proteins normally inhibit the ability of postnatal cardiomyocytes to re-enter the cell cycle. A significant increase in nuclear Yap, a key component of the Hippo pathway, accompanied the increased proliferation in the alpha-cat DKO hearts. Importantly, we found that alpha-cat DKO mice exhibit improved cardiac function following myocardial infarction compared to their control littermates. We hypothesize that loss of ?/?catenin causes cytoskeletal rearrangement and loss of tensional stress resulting in translocation of Yap to the nucleus where it activates genes critical for cardiomyocyte proliferation. The following interrelated aims are proposed: (1) To determine the cytoskeletal-based signaling pathways that regulate the cellular activity of Yap. (2) To define the functional relationship between N-cadherin/alpha- catenin/cytoskeleton interactions and myocyte elasticity and proliferation. Deformable N-cadherin- coated hydrogels will be used to determine how stiffness and N-cadherin/catenin-mediated cytoskeletal organization cooperate to regulate proliferation. Atomic force microscopy (AFM) will be used to measure cell and tissue stiffness in alpha-cat DKO under different physiological and pathological conditions. (3) In order to pursue clinical application, we will determine the window of opportunity for manipulating alpha-catenin/Yap pathway after myocardial infarction. The long term goal of this research is to determine if interfering with the cytoskeletal proteins, alpha-catenins, represents a potential therapy to enhance cardiac repair in heart failure patients.